The major goal of this Program Project Grant (PPG) is to continue to expand and further develop a vigorous research program focused on elucidating the etiology and pathogenesis of frontotemporal dementias (FTDs) tauopathies and other neurodegenerative variants of FTDs. During the last funding cycle, a close-knit and highly integrated multidisciplinary group of investigators formed a productive collaborative alliance and established a very comprehensive clinical and basic science research center-without-walls to study patients with FTDs. During the next funding period of this PPG, these seasoned investigators and young faculty newly recruited to the PPG propose a set of bold new objectives for FTD research that will be implemented through 3 Cores and 4 Projects. Specifically, they will characterize the spectrum of the clinical phenotypes seen in FTD patients, identify new mutations in FTD kindreds, elucidate mechanism of tau fibrillization, determine the building blocks ofubiquitin positive but tau, alpha-synuclein and neurofilament negative inclusions in FTD with or without motor neuron disease, and develop transgenic mouse and Co elegans models with greater versimilitude to human tau pathologies thereby leading to improvements in understanding FTDs as well as the diagnosis and treatment of these disorders.